Fluometuron Registration Review Human Health Assessment Scoping Document



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON

, D

. C

. 20460 D430248

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTIO N



### MEMORANDUM

Date: 02-MAR-2016



### SUBJECT: Fluometuron. Human Health Assessment Scoping Document in Support of Registration Review.

PC Code: 035503 DP Barcodes: 0430248; D391415 Decision No.: 511228 Registration No.: N I A
Petition No.: N I A Regulatory Action: Registration Review Scoping Document Risk Assessment Type: N I A Case No.: 0040
TXR No.: N I A CAS No.: 2164-17-2
MRID No.: 48491201 40 CFR: §180.229



### FROM: 

# I

. Julie Van Alstine

, Environmental Health

### Scientist**~** Shalu Shelat

, Environmental Healtty.Scienti§.l:**~Q~** 

### \.• o

_ 

### Nancy McCarroll

, To x icologist

### ~~IA**c~** Risk Assessment Branch VI (RABVI) Health Effects Division (HED, 7509P)



### THROUGH: Donna Davis

, Acting Branch Chief RABVl / HED (7509P)



### TO: Kelly Sherman

, Tracy Perry

, and Linsey Walsh Risk Management & 

### Implementation Branch 3 Pesticide Re-Evaluation Division (PRD; 7508P)

Attached is HED ' s human health risk assessment scoping document for fluometuron to support Registration Re v iew.

Page I of33Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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### Table of Contents
Executive Summary ............................................................................................................. ........... 3 1.0 Introduction ............................................................................................................. ................. 4 2.0 Hazard Characterization/Assessment ....................................................................................... 4 3.0 Residue Chemistry ........................................................................................................ ........... 5 4.0 Dietary Exposure ......................................................................................................... ............ 7 5.0 Residential Exposure ..................................................................................................... .......... 8 6.0 Non-occupational and Bystander Exposure .............................................................................. 8 7.0 Aggregate Risk Assessment ................................................................................................ ..... 8 8.0 Occupational Exposure .................................................................................................... ........ 9 9.0 Public Health and Pes ticide Epidemiology Data ................................................................... 10 10.0 Tolerance Assessment and International Harmonization .................................................... 11 11.0 Environmental Justice ................................................................................................... ....... 11 12.0 Cumulative .............................................................................................................. ............. 11 13.0 Human Studies ........................................................................................................... .......... 12 14.0 Risk Assessment Updates and Data Deficiencies ................................................................ 12 15.0 References .............................................................................................................. .............. 13 16.0 Attachments .............................................................................................................. ............ 13 Attachment 1: Chemical Identity Tables. .................................................................................... 1 5 Attachment 2: Fluometuron Acute, Subchr onic, and Chronic Toxicity Profile. ......................... 19 Attachment 3: Summary of Toxicological Doses and Endpoints for Fluometuron (From 2005 Risk Assessment). ............................................................................................................. ............ 24 Attachment 4: Summary of Regi stered Uses for Fluometuron. ................................................... 26 Attachment 5: DFR Waiver Criteria. ........................................................................................... 27 Attachment 6: Fluometuron Internati onal Residue Limit Status Sheet. ...................................... 28 Attachment 7. Bovine Liver and Milk Hydroxyl ated Metabolite Storage Stability Data ........... 29 Attachment 8. Status of Chemistry Defici encies Identified During Reregistration ..................... 31 Attachment 9. Submittal of Analytic al Reference Standards (860.1650) .................................... 33Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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### Executive Summary

HED has prepared a scoping document to suppo rt Registration Review of the herbicide fluometuron [ N

, N -dimethyl- N ’-(3-(trifluoromethyl) phenyl)urea]. Fluometuron is a preplant, preemergence, and/or postemergence phenylurea he rbicide for the selective control of broadleaf weeds and annual grasses. In a ddition to a Section 3 use on cotton, fluometuron is registered as a Special Local Needs (SLN) use on wildflowers in North Carolina (EPA Reg No. NC 120002). Products containing fluometuron ar e formulated as soluble concen trates (SC) and liquids (L), and may be applied as broadcast, band, over-t he-top spray, semi-directed, directed, preplant, preemergence, postemergence, or layby treatmen ts. The most recent human health risk assessment for fluometuron was performed in 2005 entitled “Fluometuron: Revised HED Risk Assessment for Phase III of the Reregistration Eligibility Decision (RED)” (E. Reaves, D341152, 2/1/2005).

HED has evaluated the status of the human h ealth assessments for fluometuron to determine whether sufficient data are available, and whether any updates are needed to support Registration Review. HED has considered all available da ta and human health risk assessments for fluometuron with respect to its toxicity, exposure, and usage databases, and the most updated Agency science policy and risk assessment me thodologies to determine the scope of work necessary to support Registration Review.

The toxicology database for fluo meturon is complete and adeq uate to support Registration Review. No additional data are required. As part of Registration Revi ew, the endpoints, doses, and safety factors used in the most recent risk assessment will be re-evaluated according to current HED policy.

The residue chemistry database is sufficient to support the current registrations. No additional residue chemistry data are re quired; however, analytical standards for the fluometuron metabolites are not available at this time a nd should be submitted. Additionally, one label contains a gin trash livestock feeding restri ction that should be removed (EPA Reg. No. 66330- 260). Fluometuron is registered for use on cotton and tolerances are established for residues of fluometuron in cotton and livestock commodities. Cereal grains, peanuts, rice, and soybeans are registered as rotational crops and inadvertent tolerances ar e established for residues of fluometuron in these commodities. There are no Codex or Canadian maximum residue limits (MRLs) established for residues of fluometuron; therefore, harmoni zation is not an issue at this time. The tolerance expressions in 40 CFR §180.229 have not been updated to reflect current HED policies and will need to be revised during Registration Review.

The most recent acute and chronic dietary risk es timates were below HED’s level of concern for the general U.S. population and all population subgroups examined. The most recent cancer dietary (food and water) risk estimate was 1.24 x 10 -5 

### . Drinking water was a driver in the cancer assessment. As part of Registration Review, updated acute, chronic, an d cancer dietary exposure and risk assessments may be required. These asse ssments should incorporat e updated percent crop treated (PCT) data (including pe rcent crop rotated data), monitoring data (if available), updated estimated drinking water concentrations (EDWCs ) from EFED, the most recent dietary exposure assessment model, and any revised toxi cological points of departure (PODs).Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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### There are no proposed or current registrations for products containing fl uometuron that allow residential use. Therefore, residential handler and post-application exposure assessments will not be needed during Registration Review.

The need for spray drift and volatilization risk assessments for fluometuron will be examined during Registration Review.

In accordance with the Food Qua lity Protection Act (FQPA), HED must consider and aggregate (add) pesticide exposures and risks from th ree major sources: food, drinking water, and residential exposures. Because there are no resi dential uses for fluometuron, only food and water were included in previous aggregate assessments. There is sufficient information available to assess aggregate exposure; however, a new aggr egate risk assessment may be required during Registration Review if the dietary exposure anal yses are updated to reflect revised PCT data, monitoring data, EDWCs, or a new dietary exposure assessment model, and/or the PODs are revised.

The occupational exposure database is adequate to support the Registration Review process for fluometuron. The most recent occupational hand ler and post-application exposure assessments are not reflective of current exposure policies an d data, but did not identify risks of concern (MOEs ≥ 100). During Registration Review, upda ted occupational handler dermal and inhalation assessments may be conducted to refl ect all currently registered uses and maximum application rates, using current occupationa l and residential expos ure (ORE) policies and updated toxicological PODs. Additionally, th e SLN label (NC 120002) should be updated to indicate that a respirator is required when fluometuron is applied with a mechanically pressurized handgun.

1.0 Introduction

Fluometuron is a preplant, preemergence, and/ or postemergence phenylurea herbicide for the selective control of broadleaf weeds and annual grasses. In addition to the Section 3 use on cotton, fluometuron is registered as a SLN use on wildflowers in North Carolina (EPA Reg No. NC 120002). HED has reviewed the most recent e xposure and risk assessments for fluometuron, as well as toxicity data, exposur e and usage databases, and the latest Agency science policy and risk assessment methodologies to determine if su fficient data are available and if updates are needed to support Registration Review.

2.0 Hazard Characterization/Assessment

When the RED was released in 2005, the toxicology database was considered adequate to characterize the toxicity of fluometuron. Since that time , however, the Toxicology Data Requirements have been revise d (40 CFR Part 158 Toxicology Data Requirements, 2007) and now include an immunotoxicity study, a subchron ic inhalation toxicity study, and acute and subchronic neurotoxicity studies. None of thes e studies are available for fluometuron. In 2013, the Hazard and Science Policy Council (HASPOC) reviewed the databases of the phenylurea herbicides, which includes fluometuron, and conc luded that immunotoxicity study data waivers could be granted for this chemical class (H abiba, 2013; TXR No. 0056795). Additionally, based on a weight-of-evidence (WOE) approach, th e HASPOC granted a data waiver for the subchronic inhalation test, with th e provision that a respirator is used to protect workers whenFluometuron Registration Review Human Health Assessment Scoping Document D430248

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### fluometuron is applied to wildflowers in NC (SLN use) with a mechanically pressurized handgun. Similarly, data waivers were granted for both the acute and subchronic neurotoxicity studies (Habiba, 2015, TXR No. 0057314).

Fluometron is slightly toxic in acute oral, dermal, and inhalation studies (Toxicity Category III). It is moderately toxic in primary eye and dermal irritation studies (Toxicity Category II). It is not, however, a dermal sensitizer.

Fluometuron induces lung adenomas and carcinomas in male mice and malignant lymphocytic lymphomas in female mice. It is classified as a Group C – possible human carcinogen and for the purposes of the risk characterizati on, both a low dose extrapolation model (Q 1 * 

### ) was applied to the animal data (lung tumors in male mice) an d the Reference Dose (RfD) approach was used. The unit risk, Q 1 * 

### (mg/kg/day) -1 

### is 1.80 x 10 -2 

### in human equivalents. No compound related tumors were observed in the rats and genotoxicity studies with fluometu ron were negative.

In other toxicology studies, the spleen, kidney, and liver appear to be the organs consistently affected following exposure to moderate doses of fluometuron in rats and dogs in subchronic, chronic, developmental, and reproductive studies. Effects in the spleen ar e consistently linked to an increased turnover of red blood cells (RBCs) and the deposition of hemosiderin pigment in the breakdown of RBCs; however, no systemic ch anges were found in male or female rabbits exposed dermally to the limit dose.

Reproductive or developmental effects in rats or rabbits were only observe d at maternally toxic doses; thus, an increased sensitivity of the young was not associated with this chemical. No developmental effects were found in rats or rabb its and no reproductive effects attributable to fluometuron were found in male or female rats.

Fluometuron was rapidly absorbed (within the firs t 24 hours), distributed to all tissues, and the majority of the radiolabel test substance was excreted in the urine wi thin the first 24 hours following dosing, with a small percentage (6 -12%) found in the feces. Fluometuron is metabolized by oxidative processes to yield a va riety of ring hydroxylated metabolites. For risk characterization, the parent (fluometuron) endpoints are used, and all metabolites of concern are calculated as fluometuron equivalents. The metabolism of fluometuron in drinking water analysis has been reviewed. The parent fluomet uron is very stable to abiotic hydrolysis and photolysis in water and on soil. It is also stable to aerobic soil metabolism, anaerobic soil metabolism, and anaerobic aquatic metabolism

Conclusions: The toxicology database for fluometur on is complete and adequate to support Registration Review. No additi onal data are required. As pa rt of Registration Review, the endpoints, doses, and safety factors used in the most recent risk assessment (Attachment 2) will be re-evaluated according to current HED policy.

3.0 Residue Chemistry

The residue chemistry database is sufficient to support the current registrations. The nature of the residue in plants and livestock is adequate ly understood. Acceptable studies depicting the qualitative nature of the residue in cotton plan ts, ruminants, and poultry have been submitted and evaluated. The HED Metabolism Committee conclude d that for plants, the residues of concernFluometuron Registration Review Human Health Assessment Scoping Document D430248

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### consist of fluometuron and its metabolites dete rmined as trifluoromethyl aniline (TFMA), and for meat, milk, poultry, and eggs, the residues of concern consist of fluometuron and its metabolites determined as TFMA and th e hydroxylated metabolites CGA-236431, CGA-236432, CGA-13211, and their conjugates (S. Funk, HED Metabolism Committee Memorandum, 2/22/1996). A detailed discussion of the nature of the residues , residue analytical methods, available field trial and proces sing data, and rotational crop studi es for fluometuron can be found in the most recent chemistry chapter (S. Ary, 11/30/2004; D300553).

Acceptable data collection methods that are capab le of determining all fluometuron residues of concern in plant (Methods AG-528 and AG-529) and livestock (Methods AG-678; AG-519; AG519A) commodities have been submitted. HED previ ously requested that the registrant either improve Method AG-519A or develop a new me thod capable of determining fluometuron residues that may be converted to TFMA in livestock commodities (S. Ary, 30-NOV-2004; D300553). Subsequently, the Registrant submitt ed a waiver request for a revised Method AG519A, and HED reviewed the supporting rationale and recommended that the study requirement be waived (Memo, P. Barnes, 4/23/2009; D300532) . The Analytical Chemistry Branch (ACB) has reviewed the available method data (without laboratory validation) for Methods 519, 519A, AG-678, AG-528, and AG-529 and concluded that the methods appear to meet the 860.1340 Residue Chemistry Test Guidelines for accepta ble tolerance enforcement methods (Memo, C. Stafford, 3/13/2009; D300532). The FDA PESTDATA database dated 10/1999 (PAM Volume I, Appendix I) indicates that fluometuron is co mpletely recovered usi ng Multiresidue Methods Section 403 (method for phe nylurea herbicides).

Adequate storage stability data are available to support the registered uses. HED previously requested storage stability data for the hydroxylated metabolites of fluometuron (CGA-236431, CGA-236432, CGA-13211) in ruminant milk and muscle (up to 269 days) and egg and poultry tissues (approximately 4 months; Memo, S. Ary, 11/30/2004; D300553). Subsequently, the ChemSAC recommended that storage stability studies on the hydroxylated metabolites be conducted for residues in ruminant liver and milk samples and that any requirement for additional poultry data be deferred until the required ruminant storage stability data had been submitted and reviewed (ChemSAC Minutes, 17-OCT-2007). ChemSAC also recommended that if the ruminant storage stab ility data indicated that residu es were stable, a poultry feeding study and storage stability data for egg and poul try tissues would not be required. Acceptable storage stability data for bovine liver and m ilk have been submitted to the Agency (MRID 48491201) and these deficiencies are now resolve d. The results of the study showed that residues of the hydroxyfluometuron meta bolites CGA-13211, C GA-235431, and CGA-235432 are stable for at least 12.9 months for liver and 12.0 months for milk when stored at or below -12 °C (see Attachment 7). Since the ruminant liver and milk data i ndicated that residues are stable for the storage duration, a poultry feeding study a nd storage stability data for egg and poultry tissues are not required at this time.

Several residue chemistry data requirements were id entified as part of Re registration (E. Reaves, 2/1/2005; D341152). Aside from one label revision, th e chemistry data defici encies identified as part of Reregistration have been adequately a ddressed (Attachment 8). The Flomet 4L label (EPA Reg. No. 66330-260) still contains a gin trash livestock feeding restri ction that should be removed since cotton gin trash is not under the control of the grower.Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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### Analytical reference standards for the parent fluometuron are currently available in EPA’s National Pesticide Standards Repository (NPSR) a nd expire on 6/30/2016. Analytical reference standards are currently unavailable in EP A’s NPSR for the following metabolites: trifluoromethylaniline (out of stock) ; CGA-236431 (expired on 6/26/2014); CGA-236432 (expired on 6/26/2014); and CGA- 13211 (expired on 6/26/2014) (E mail communication with G. Verdin of BEAD/ACB on 11/9/2015). Analytical reference standards should be submitted to the NPSR (see Attachment 9 for submission information).

Conclusions: The residue chemistry database is suffi cient to support the current registrations. Adequate metabolism (crops, livestock, and rotati onal crops), storage stab ility, magnitude of the residue, and processing data are av ailable to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances. No additional residue chemistry data are required to support the curren t registrations; however, analytical standards are required for several fluometuron metabolites (Attachment 9). A dditionally, the gin trash feeding restriction from one label should be removed (EPA Reg. No. 66330-260).

4.0 Dietary Exposure

Acute, chronic, and cancer dietary (food and dr inking water) assessments were conducted for fluometuron to support HED’s Re registration Eligibility Deci sion (RED) document (Memo, S. Ary, 9/27/2005; D321682). Estimat ed Drinking Water Concentra tion (EDWC) values were provided by the Environmental Fate and Effects Di vision (EFED) and were directly incorporated into the assessment. The dietary risk assessmen ts incorporated refined PCT data for cotton and the estimated percent of rota ted crops exposed to fluometuron. These assessments were performed using Dietary Exposure Evaluation Mode l software with the Food Commodity Intake Database (DEEM-FCID  , Version 2.03), which uses food c onsumption data from the US Department of Agriculture’s (USDA’s) Con tinuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

The acute (Monte-Carlo), chronic, and cancer a ssessments were moderately refined and used field trial anticipated residue (AR) data, PCT da ta, ARs for livestock commodities, and empirical and default processing factors. Acute dietary risk estimates were provided for females 13-49 years old only since there is no st udy to support an effect from a single dose for the general U.S. population. The acute and chronic dietary risk estimates do not exceed HED’s level of concern (less than 100% of the PAD). Th e acute dietary risk at the 99.9 th 

### exposure percentile for females 13-49 years old was 4.5% of the acute population-adjusted dose (aPAD). The chronic dietary risk estimates were 13% of the chronic populatio n-adjusted dose (cPAD) for the general U.S. population and 41% of the cPAD for all infants le ss than 1 year old, the most highly-exposed population subgroup. The cancer assessment resu lted in a fluometuron dietary (food and drinking water) exposure estimate of 0.000688 mg/ kg/day for the general U.S. population. Applying the Q 1 

### * of 1.80 x 10 -2 

### (mg/kg/day) -1 

### to the exposure value re sulted in a cancer risk estimate of 1.24 x 10 -5 

### . The significant cancer risk contributor was identified as water (direct, all sources and indirect , all sources).

Conclusions: The most recent acute and chronic dietary risk estimates were below HED’s level of concern for the general U.S. population and all po pulation subgroups examined. The most recent cancer dietary (food and wate r) risk estimate was 1.24 x 10 -5 

### . Drinking water wa s a driver in the cancer assessment. As part of Registration Review, updated acut e, chronic, and cancer dietaryFluometuron Registration Review Human Health Assessment Scoping Document D430248

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### exposure and risk assessments may be required. These assessments should incorporate updated PCT data (including percent crop rotated data), monitoring data (if av ailable), updated EDWCs from EFED, the most recent ve rsion of DEEM-FCID, and any revised toxicological PODs.

5.0 Residential Exposure

There are no registered or propos ed fluometuron products that allo w residential use; therefore, a quantitative residential exposur e assessment was not conducted.

Conclusions: There are no proposed or current regist rations for products c ontaining fluometuron that allow residential use. Therefore, re sidential handler and pos t-application exposure assessments will not be needed during Registration Review.

6.0 Non-occupational and Bystander Exposure

Residential bystander exposures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result of applications of fluometur on. The potential for spray drift will be quantitatively evaluated for each pestic ide during the Registration Review process that ensures that all uses for that pesticide will be co nsidered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures for Reside ntial Risk Assessment (SOPs) – Residential Exposure Assessment Standard Operati ng Procedures Addenda 1: Consideration of Spray Drift. This document out lines the quantification of indi rect non-occupational exposure to drift.

In terms of volatilizatio n, the Agency has developed a Vola tilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#! docketDetail;D=EPA-HQ-OPP-2014- 0219). During Registration Review, the Agency will u tilize this analysis to determine if da ta (i.e., flux studies, route-specific inhalation toxicological studies ) or further analyses are required for specific chemicals.

Conclusions: The need for spray drift and volatilization risk assessment for fluometuron will be examined during Registration Review.

7.0 Aggregate Risk Assessment

In accordance with FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, a nd residential exposures. The most recent aggregate risk assessment for currently regist ered uses of fluometuron was performed in conjunction with the 2005 Revised HED Risk As sessment for Phase III of the Reregistration Eligibility Decision (RED) (E . Reaves., 2/1/05, D341152). The Agency conducts aggregate exposure assessments by summing dietary (food and wa ter) and residential e xposures (residential or other non-occupational exposures). Since there are no registered /proposed uses of fluometuron that result in resi dential exposure, the chronic and cancer aggregate risk assessments are equal to the chronic and cance r dietary estimates (food and wate r only), respectively. Short-, intermediate-, and long-term aggregate-risk as sessments were not performed because there are no registered or proposed uses of fluometur on that result in resi dential exposures.Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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### Conclusions: As part of Registration Review, update d aggregate exposure and risk assessments are recommended. These assessments should reflect revised dietary exposu re estimates and/or any revisions to the toxicological PODs.

8.0 Occupational Exposure

Fluometuron is registered for use on cotton. Attachment 4 provides a summary of the occupational use pattern. Fluometur on is currently registered as two technical formulations and four end use products formulated as a liquid with a maximum application rate of 2 lbs ai/acre. Additionally, fluometuron is registered for one SL N use on wildflowers at an application of 1 lbs ai/acre or 0.1 lbs ai/gallon. The HASPOC gran ted a data waiver for a subchronic inhalation study, with the provision that a re spirator is used to protect wo rkers when fluometuron is applied with a mechanically pressurized handgun to wildflowers in NC for the SLN use. Fluometuron applications can be made using aeria l, ground, and handheld applications.

Based on the registered use patter ns, there is a potential for derm al and inhalation exposure to fluometuron in occupational scenarios from handling fluometuron products during the application process (i.e., mixer/lo aders, applicators, and flaggers). The labels currently require mixer and loaders to wear baseline attire (i.e., long-sleeved shirt, long pants, socks, and shoes) along with coveralls and gloves for aerial applications. All othe r handlers must wear baseline attire with the addition of gloves, except applicators and flaggers.

In addition, there is a potentia l for post-application worker e xposure from entering into areas previously treated with fluometuron. The curre nt restricted entry in terval (REI) for postapplication activities is 24 hours.

Occupational Handlers: In the 2005 risk assessment (E. Reaves, D341152, 2/5/2005) for fluometuron, an occupational handler assessmen t was conducted for the use on cotton at the maximum application rate of 2 lbs ai/acre. There were no non-can cer risk estimates of concern identified at that time at some level of risk mitigation. The cancer handler exposure and risk assessment was conducted at the average application rate of 1.5 lbs ai/acre. The days per year assumption (6 days for private applicators and 18 days for commercial applicators) were a deviation from the current policy. The handler ca ncer assessment for both dermal and inhalation cancer risks ranged from 2 x 10 -6 

### to 2 x 10 -4 

### at some level of risk mitigation.

The 2005 risk assessment may not reflect the mo st up-to-date exposure data or inputs for occupational handlers. An updated occupational handler dermal and inhalation assessment may be conducted as part of Regi stration Review to reflect current ORE policies and updated toxicological PODs. The occupa tional exposure assessment should consider the provision that a respirator is used to protect workers when fluometuron is app lied to wildflowers in NC (SLN use) with a mechanically pressurized handgun.

Occupational Post-application: In the 2005 risk assessment for fluometuron, an occupational post-application assessment was conducted for po st-application ac tivities including irrigation, scouting, and hand weeding. No chemical-specific dislodgeable foliar residue data is available. Post-application risk estimates we re not of concern (i.e., MOEs ≥ 100) on the day of treatment (i.e., Day 0) for all post-application exposure activities. The pos t-application cancer assessmentFluometuron Registration Review Human Health Assessment Scoping Document D430248

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### was conducted with the average appl ication rate of 1.5 lbs ai/acre. The days per year assumption (6 days) is a deviation from the current policy. The 2005 asse ssment reported post-application risks for early season entry less than 1 x 10 -6 

### on day 0, approximately 12 hours following application. The post-application cancer risks for later season entry are less than 1 x 10 -4 

### on day 0 and are less than 1 x 10 -6 

### on day 12.

Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide ha s occupational uses that could result in post-application dermal exposure. Since the highest estimated occupational postapplication exposure using default DFR values fo r fluometuron is minimal in comparison to the level of concern (i.e., the calcu lated MOE is greater than 2 times higher than the level of concern, MOE = 730 compared to the LOC of 100); EPA is waiving the 40CFR DFR data requirement. In this instance, it is unlikely that chemical-specific DFR data would be needed to further refine exposure assessments or would ad d appreciably to our ove rall understanding of the availability of dislodgeable folia r pesticide residues for fluometuron. Additional information is provided in Attachment 5.

Conclusions: The occupational exposure database is adequate to support the Registration Review process for fluometuron. The most r ecent occupational handler and post-application exposure assessments may not be reflective of current exposure policies and data. During Registration Review, updated occupational handle r dermal and inhalation assessments and a dermal post-application assessment may be conducte d to reflect all currently registered uses and maximum application rates, current ORE polic ies, and/or updated toxicological PODs. Additionally, the SLN label (NC 120002) should be updated to indica te that a respirator is required when fluometuron is applied with a mechanically pressurized handgun.

9.0 Public Health and Pesticide Epidemiology Data

The OPP Incident Data System (IDS) a nd the Centers for Disease Control and Prevention/National Institute for Occupational Sa fety and Health (CDC/N IOSH) Sentinel Event Notification System for Occupational Risk-Pestic ides (SENSOR) databases were consulted for pesticide incident data on the active ingredient fluometuron (Memo, E. Evans et al. , 03/03/2016; D431967). The purpose of the database search is to identify potential patterns in the frequency and severity of the health eff ects attributed to fluometuron exposure. Fluometuron is not included in the Agricultural Health Study (AHS ), and therefore this study does not provide information for this report.

The OPP IDS records incidents in one of two modules: the Main IDS and the Aggregate IDS. The Main IDS contains incidents resulting in higher severity out comes and provides more detail with regard to case specifics. The Aggregate IDS contains incidents re sulting in less severe human incidents (minor, unknown, or no effects outcomes). For the Main IDS, from January 1, 2010 to September 25, 2015, there were no incidents reported for fluometuron in the database. For the Aggregate IDS, from January 1, 2010 to September 25, 2015, there was one incident reported involving fluometuron. Th is incident was classified as minor severity. Overall, there are few incidents reported to IDS involving fluometuron.

The SENSOR-Pesticides database covers 12 st ates from 1998-2011, although reporting varies from state to state. Cases of pesticide-related illnesses are asce rtained from a variety of sources,Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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### including: reports from local Poison Control Centers, state Department of Labor workers’ compensation claims when reported by physicia ns, reports from State Departments of Agriculture, and physician reports to state Departments of He alth. A review of SENSORPesticides from 1998-2011 identifies no cases involving fluometuron.

Conclusions: Based on the low frequency and seve rity of incident cases reported for fluometuron in both IDS and SENSOR-Pesticides ther e does not appear to be a concern at this time that would warrant further investigation. Th e Agency will continue to monitor the incident information and if a concern is triggered, additiona l analysis will be included in risk assessments for fluometuron.

10.0 Tolerance Assessment and International Harmonization

Fluometuron is registered for use on cotton and tolerances are estab lished for residues of fluometuron in cotton and livestock commodities. Cereal grains, peanuts, rice, and soybeans are registered as rotational crops a nd inadvertent tolerances are al so established for residues of fluometuron in these commodities. There are no Codex or Canadian MRLs established for residues of fluometuron; therefore, harmonization is not an issue at this time. The fluometuron International Residue Limit Status Sheet is availa ble in Attachment 6. Th e tolerance expressions in 40 CFR§180.229 have not been updated to reflect current HED policies and will need to be revised during Registration Review.

11.0 Environmental Justice

Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the most recent fluometuron human h ealth risk assessment, in accord ance with U.S. Executive Order 12898, “Federal Actions to Addre ss Environmental Justice in Minority Populations and LowIncome Populations a 

### .” The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from s ources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potenti al risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are ba sed on the best available information.

12.0 Cumulative

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fluometuron and any other substances and fluometuron does not app ear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fluometuron has a common mechanism of to xicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pestic ides/cumulative/.

a http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdfFluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 12 of 33 

### 13.0 Human Studies

Past fluometuron risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pest icide to determine their dermal and inhalation exposure. Many such studies, i nvolving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pest icide Handlers Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF) Database, and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporti ng these multi-pesticide generic exposure databases, and has found no cl ear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research wa s conducted. All applicab le requirements of EPA’s Rule for the Protection of Human Subject s of Research (40 CFR Part 26) have been satisfied, and there is no re gulatory barrier to continue d reliance on these studies.

14.0 Risk Assessment Update s and Data Deficiencies

No toxicology or occupational/residential expos ure data deficiencies were identified for fluometuron. Two required label updates and on e residue chemistry deficiency have been identified for fluometuron and should be addr essed as part of Re gistration Review:

 The Flomet 4L label (EPA Reg. No. 66330- 260) should be revised to remove the livestock gin trash feeding restriction since cotton gi n trash is not under the control of the

grower.

 The SLN label (NC 120002) should be updated to indicate that a respirator is required when fluometuron is applied with a mechanically pressurized handgun.

 Analytical reference standards should be submitted to EPA’s NPSR for the following fluometuron metabolites: tr ifluoromethylaniline (out of stock); CGA-236431 (expired on 6/26/2014); CGA-236432 (expired on 6/ 26/2014); and CGA-13211 (expired on 6/26/2014). See Attachment 9 fo r submission instructions.

Additionally, EPA notes the following risk assessment updates may be needed during Registration Review:

 Toxicology:

o Re-evaluation of endpoints, doses, and sa fety factors to reflect current HED policies.

 Residue Chemistry/Dietary Exposure:

o Updated acute, chronic, and cancer dietar y exposure and risk assessments that incorporate updated PCT data (including perc ent crop rotated data), monitoring data (if available), updated EDWCs from EFED , the most recent version of DEEMFCID, and any revised toxicological PODs.

o Updated tolerance expressions in 40 CFR §180.229 to reflect current HED policies.

 Occupational/Residen tial Exposure:

o Spray drift and volatilization risk assessments to reflect current HED policies.

o Updated occupational handler dermal a nd inhalation assessments and a dermal post-application assessment that refl ect all currently registered uses, maximumFluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 13 of 33 

### application rates, current ORE policies, and/or updated toxicological PODs

 Aggregate Exposure:

o Updated aggregate exposure analyses to re flect revised dietary exposure estimates and/or any revisions to the toxicological PODs.

15.0 References

Memoranda Relevant to Registration Review.

Author DP Barcode Date Title

E. Reaves D341152 2/1/2005 Fluometuron: Revised HED Risk Assessment for Phase III of the Reregistration Eligibility Decision (RED).

B. Smith D300551 12/7/2004 Fluometuron: Occupational Exposure Assessment for the Reregistration Eligibility Decision Document.

S. Ary D300553 11/30/2004 Fluometuron. Summary of Analytical Chemistry and Residue Data for the Reregistration Eligibility Decision (RED) Document.

U. Habiba TXR No. 0056795 9/25/2013 Forchlorfenuron and Phenyl Urea Herbicides: Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 12, 2013: Recommendations on the Data Requirement for an Immunotoxicity Study for Forchlorfenuron and for the Ph enyl Urea Herbicides as a Class.

S. Gallagher TXR No. 0057314 02/16/2016 Fluometuron: Summary of Hazard and Science Policy Council (HASPOC) Meeting of November 12, 2015: Recommendations on the Requ irement for Subchronic Inhalation and Acute and Subchronic Neurotoxicity Studies.

S. Ary D321682 9/27/2005 Fluometuron. Revised Acute, Chronic, and Cancer Dietary Exposure Assessments for the Reregistration Eligibility Decision (RED) Document.
S. Funk -- 2/22/1996 HED Metabolism Committee Memorandum

P. Barnes D300532 4/23/2009 Fluometuron. Review of data submitted by MakhteshimAgan of North America Inc. in response to the Health Effects Division (HED) data requirements and tolerance reassessment considerations in cluded in the RED, Docket Number EPA-HQ-OPP-2004-0372 dated November 2005. (Federal Register: January 31, 2007 (Volume 72, Number 20))
E. Evans et al. D431967 03/03/2016 Fluometuron: Tier I (Scoping) Review of Human Incidents and Epidemiology



### 16.0 Attachments Attachment 1: Chemical Identity Tables. Attachment 2: Fluometuron Acute, Subc hronic, and Chronic Toxicity Profile. Attachment 3: Summary of Toxicological Doses and Endpoints for Fluometuron (from 2005 Risk Assessment). Attachment 4: Summary of Re gistered Uses for Fluometuron. Attachment 5: DFR Waiver Criteria. Attachment 6: Fluometuron Internat ional Residue Limit Status Sheet. Attachment 7. Bovine Liver and Milk Hydr oxylated Metabolite Storage Stability Data. Attachment 8. Discussion of Chemistry Defi ciencies Identified During Reregistration. Attachment 9. Submittal of Analy tical Reference Standards (860.1650).Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 14 of 33 cc: J. Van Alstine (RAB6), S. Sh elat (RAB6), N. McCarroll (RAB6) RDI: D. Davis (11/20/15), J. Rowland (11/24/15), J. Dawson (11/25/15) J. L.Van Alstine:S-10217:PY-S:(703)603-8866:7509P:RAB6Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 15 of 33 

### Attachment 1: Chemic al Identity Tables.

Table A.1.1. Test Compound Nomenclature.

Chemical structure

Common name Fluometuron
Empirical formula C 10 H 11 F 3 N 2 O

IUPAC name 1,1-dimethyl-3-( α , α , α -trifluoro- m -tolyl)urea

CAS name N

, N

-dimethyl- N ’-(3-(trifluoromethyl)phenyl)urea

CAS number 2164-17-2

PC Code 035503
End-use products (EP) Cotton [66222-32; 66222-181; 66330-260; 83529-33; NC120002]; Wildflowers [NC 120002]

Table A.1.2. Physicochemical Properties of the Technical Grade Test Compound.

Parameter Value Reference
Molecular weight 232.20 Merck Index

pH Not available
UV/visible absorption Not available
Melting point/melting range 163-164.5  C MRID 00019017
Density 1.40 ± 0.02 g/cm 3 at 20  C MRID 00019017

Dissociation constant in water No dissociation MRID 42017302
Octanol/water partition coefficient 242 (log P = 2.38) MRID 00160757
Water solubility 105 ppm at 20  C MRID 00152460
Solvent solubility Acetone 15%, Chloroform 2%, Hexane less than 4%, Methanol 14%, Methylene 2% at 20  C MRID 00019017

Vapor pressure 5 x 10 -7 mm Hg at 20  C MRID 00019017Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 16 of 33 Table A.1.3. Chemical Names and Structures of Fluometuron and Its Metabolites.

Common Name Chemical Name Chemical Structure

Fluometuron 1,1-dimethyl-3-( α , α , α -trifluoro-m-tolyl)urea

CGA-41686 1-methyl-3-( α , α , α -trifluoro-m-tolyl)urea

CGA-41685 1-( α , α , α -trifluoro-m-tolyl)urea

Lysine Conjugate of CGA-41685

Phospholipid Conjugate of CGA-41685

CGA-132111,1-dimethyl-3-(4-hydroxy-3-trifluoromethylphenyl)ureaFluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 17 of 33 Table A.1.3. Chemical Names and Structures of Fluometuron and Its Metabolites.

Common Name Chemical Name Chemical Structure

CGA-236431 1-(4-hydroxy-3-trifluoromethyl-phenyl)urea

Sulfate Conjugate of CGA-236431

CGA-2364321-methyl-3-(4-hydroxy-3-trifluoromethylphenyl)urea

Sulfate Conjugate of CGA-236432

CGA-72903 Trifluoromethyl aniline (TFMA)Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 18 of 33 Table A.1.3. Chemical Names and Structures of Fluometuron and Its Metabolites.

Common Name Chemical Name Chemical Structure

CGA-21835 1-formyl-1-methyl-3-( α , α , α -trifluoro-mtolyl)urea

N-demethylated CGA-21835 1-formyl-3-( α , α , α -trifluoro-m-tolyl)ureaFluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 19 of 33 

### Attachment 2: Fluometuron Acute, Subc hronic, and Chronic Toxicity Profile.

A.2.1 Toxicology Data Requirements The requirements (CFR 158.340) for a food use for fluometuron are in Table A.2.1. Use of the new guideline numbers does not imply that ne w (1998) guideline protocols were used.

Table A.2.1: Toxicology da ta requirements for a food use pesticide and whether or not they have been satisfied.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity ...................................................... 870.1200 Acute Derm al Toxicity ................................................. 870.1300 Acute Inhala tion Toxic ity ............................................. 870.2400 Primary Ey e Irrita tion ................................................... 870.2500 Primary Derm al Irrita tion ............................................. 870.2600 Dermal Sensitiza tion .................................................... yes yes yes yes yes yes yes yes yes yes yes yes
870.3100 Oral Subchronic (rodent) .............................................. 870.3150 Oral Subchronic (nonrodent) ........................................ 870.3200 21-Day Dermal ............................................................. 870.3250 90-Day Dermal ............................................................. 870.3465 90-Day Inhalation ......................................................... yes yes yes

no yes yes yes yes

no

no 1

870.3700a Developmental Toxicity (rodent) ................................. 870.3700b Developmental To xicity (non rodent) ........................... 870.3800 Repr oduction ................................................................ yes yes yes yes yes yes

870.4100a Chronic To xicity (rodent) ............................................. 8xicity 70.4100b Chronic To xicity (non rodent) ............................. 870.4200a Oncogenicity (rat) ........................................................ 870.4200b Oncogenic ity (mous e) .................................................. 870.4300 Chronic/On cogenicity .................................................. yes yes yes yes yes yes yes yes 1
No
yes
870.5100 Mutagenicity—Gene Mutation - b acterial .................... 870.5300 Mutagenicity—Gen e Mutation - mammalian .............. 870.5xxx Mutagenicity—Structural Chromosomal Aberrations .. 870.5xxx Mutagenicity—Other Genotoxic Effects ...................... yes yes yes

no yes yes yes

no
870.6100a Acute Delaye d Neurotox. (hen) .................................... 870.6100b 90-Day Neur otoxicity (hen) ......................................... 870.6200a Acute Neurotox. Sc reening Battery (rat) ...................... 870.6200b 90 Day Neuro. Sc reening Batter y (rat) ......................... 870.6300 Develo p. Neuro ............................................................ no 2

no 2

yes yes

no -

-
no 1

no 1

no

870.7485 General Metabolis m ..................................................... 870.7600 Dermal Penetra tion ....................................................... yes

no yes

no 870.7800 Immunotoxicity (rat) yes no 3

1 Data waivers granted by HASPOC (U. Habiba, 2015; TXR No. 0057314) for subchronic inhalation study and for the acute and subchronic neurotoxicity studies.

2 Required only for organophosphate pesticides

3 Data waiver granted for immunotoxicity study (U. Habiba, 2013; TXR 0056795).Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 20 of 33 

### A.2.2 Toxicity Profiles

The toxicology data for the acute toxicity studi es with fluometuron (80 to 85% end use product) b 

### are listed in Table A.2.2. The toxicity profile fo r fluometuron is presented in Table A.2.3.

Table A.2.2: Acute Toxicit y of Fluometuron. Guideline No./Study Type MRID No. Results Toxicity Category 870.1100 /Acute Oral (Rats) 40409302 (1987)

41216802

(1989) 80% LD 50 = 5223 mg/kg (M &F)

85% LD 50 = 3880 mg/kg (M) & >1000 mg/kg (F) IV

III

870.1200 Acute Dermal (Rabbit) 40409303 (1987)

41216803

(1989) 80% LD 50 = >2 g/kg (M& F)

85% LD 50 = 2020 mg/kg (M& F) III

III

870.1300 Acute Inhalation (Rat) 40409304 (1987)

41216804

(1989) 80% LC 50 >0.6 mg/L

85% LC 50 >2.25 mg/L III

IV 870.2400 Primary Eye Irritation (Rabbit) 40409305 (1987)

41216805

(1989) 80% Corneal opacity, iris irritation, chemosis, discharge cleared day 7 in unwashed group; 72 hours in washed group

85% Corneal opacity cleared day 4; conjunctival irritation cleared day 10. II

II

870.2500 Primary Skin Irritation (Rabbit) 40409306 (1987)

41216806

(1989) 80%

Slight erythema

85% Slightly irritating w/eschar, PIS = 0.96 II

II

870.2600 Dermal Sensitization (Guinea Pig) 40409307 (1987)

41216807

(1989) 80% Non-sensitizing

85% Non-sensitizing NA

Table A.2.3. Toxicity Profile of Fluometuron

Study Type MRID No. Results

870. 3100 90-daysubchronicfeeding-rat 00019034 (1965) Acceptable/guideline 0, 100, 1000 & 10,000

ppm NOAEL = 8.2/7.8 mg/kg/day (100 ppm) LOAEL = 84/89 mg/kg/day, based on enlarged spleen and dark kidneys, which was more severe at the HDT.

b End use product (80 or 85%) used for the acute studiesFluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 21 of 33 Table A.2.3. Toxicity Profile of Fluometuron

Study Type MRID No. Results (0, 8.2/7.8, 84/89 &765/789 mg/kg/day (M&F)

870. 3150
13-weeksubchronicfeeding-dog 00019035 (1965) Acceptable/guideline 0, 40, 400 & 4000 ppm 0, 1.5, 10 & 150 mg/kg/day (M & F) NOAEL= 10 mg/kg (400 ppm) LOAEL = 150 mg/kg (4000 ppm), based on inflammatory reactions in the liver and kidney.

870. 3200 21-day dermal toxicity-rabbit 00160763 (1964) Acceptable/guideline 0, 10, 1000 & 1000 mg/kg/day (M & F) NOAEL = 1000 mg/kg (HDT) No systemic or toxicity was seen at any dose tested. No LOAEL established.

870.3465 90-day Inhalation Data waiver granted by HASPOC (Habiba, U, 2015; TXR No. 0057314).

870. 4100
ChronicFeeding-Dog 40779001 (1988) 41189501 (1988) Acceptable/guideline 0, 20, 400 & 7000 ppm (0, 0.6/0.7, 14/13 & 237/237 mg/kg/day M/F NOAEL = 14/13 [M/F] mg/kg (400 ppm) LOAEL= 237 [M&F] mg/kg (7000 ppm), based on decreased body weight, food consumption, hemoglobin, hematocrit, RBC’s; increases in total bilirubin, Heinz & Howell-Jolly bodies, increased relative and absolute liver weight.

870. 4200CarcinogenicityMouse 00163845 (1986) 42413501 (1992) 43506601 (1994) Unacceptable 0, 10, 500 & 2000 ppm (0, 1.2/1.4, 61.5/83.9 & 260/265.8 mg/kg/day M & F) Study does not satisfy guideline requirement 83-2b for carcinogenicity testing in mice. NOAEL = 2000 ppm, the highest dose tested, based on the lack of any significant systemic toxi city. Significant increasing trend in alveolar/bronchiolar adenomas and/or carcinomas in males combined at p <0.05. Significant increasing trend and a pairwise comparison of the 2000 ppm group with controls for lymphocytic lymphomas at p < 0.05 in females.

The RfD Committee considered the high dose to be inadequate for carcinogenicity testing; the HED Carcinogenicity Peer Review Committee (CPRC) concluded that the statistically significant increases in combin ed adenomas/carcinomas of the lungs in male mice and malignant lymphocytic lymphomas in female mice were observed at a dose that was less than adequate for fully assessing the carcinogenic potential of fluometuron (Taylor and Van Gemert, 1995 ; Spencer & Burnam, 1995); Taylor and Rinde, 1996) c

Based on these data, CPRC concluded that fluometuron should be classified as Group C (Possible Human Carcinogen) with a Q 1 * (mg/kg/day) of 1.80 x 10 -1 in human equivalents (3/4’s scaling factor to convert from animal to humans) (Taylor and Rinde, 1996)

c Taylor, L.L. and Van Germet, M. (1995). Toxicology Endpoint Selection Document, dated April 20, 1995. Spencer, H. W. and Burnam, W. (1995). Fluometuron: RfD/Peer Review Report, data July 20, 1995. Taylor, L.L. and Rinde, E. (1996). Carcinogenicity Peer Review of Fluometuron, dated August 28, 1996. TXR No. 0012049.Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 22 of 33 Table A.2.3. Toxicity Profile of Fluometuron

Study Type MRID No. Results

870. 4300
Chronic toxicity/ Carcinogenicity
-Rat 00163772 (1982) Acceptable/guideline 0, 10, 300 & 1000 ppm (0, 0.55/0.69, 17.17/21.20 & 59.21/70.76 mg/kg/day M/F) NOAEL= 10 ppm (0.55/0.69 [M/F] mg/kg) LOAEL= 300 ppm (17.2/21.2 [M/F] mg/kg), based on hemosiderin deposition in the spleen.

MTD= 1000 ppm based on reduced body weight gain. A histological re-examination resulted in statistically significant increases in pituitary adenomas in male rats at all doses; however, there was no significant trend, the response was flat.

The RfD Committee considered the dose levels to be adequate [memo dated 12/09/93]. Satisfies guideline requirements (83-1a and 83-2a) for chronic toxicity/car cinogenicity testing in rats. No clear evidence of a carcinogenic effect in rats

870.3700a Developmental Toxicity-Rat 00163710 (1988)/ 423897601 (1992) Acceptable/guideline 0, 10, 100 & 1000 mg/kg/day on GDs 6-15 Maternal NOAEL= 10 mg/kg LOAEL= 100 mg/kg, based on the reduction of food consumption and on the increased darkened spleen.

Developmental NOAEL= 10 mg/kg Developmental LOAEL= 100 mg/kg, based on an increased delayed urinary system development (shortened renal papillae). Females at 1000 mg/kg/day also exhibited: reduced body weight, reduced viability, lethargy & salivation.

Fetal abnormalities at 1000 mg/kg/day included reduced fetal wei g increased resorptions & postimplantation loss, and skeletal abnormalities. 870.3700b Developmental Toxicity-Rabbit 00163774 (1986) 00147554 (1984) 42397602 (1992) Acceptable/guideline 0, 1, 10 100 mg/kg/day on GDs 7-19 Maternal NOAEL= 10 mg/kg LOAEL= 100 mg/kg, based on increased incidence of stool variations and abortions, reduced food consumption, decreased maternal body wt. gain. Developmental NOAEL= 100 mg/kg (HDT) No developmental toxicity was observed. 870.3800 Reproductive Toxicity Rat 2-generation 00163773 (1982) Acceptable/nonguideline 0, 10, 300 & 1000 ppm (0, 0.5, 15 & 50 mg/kg/day M & F) Note: Study investigated 3 generations Systemic (Parental) NOAEL= 0.5mg/kg (10 ppm) LOAEL= 15 mg/kg (300 ppm), based on spleen effects(extramedullary hematopoiesis, and an increase in hemosiderinladen macrophages).

Reproductive NOAEL= Study not rigorous enough to base a conclusion on whether Fluometuron has the potential to affect reproductive performance.

RfD Committee concluded study is adequate for risk assessment

purposes. (TXR 010710) d
870.5100
Gene Mutation – 40802901 (1988) Negative for gene mutation in Salmonella strains TA100, TA98, TA1537, and TA1535 exposed up to 5000 μg/plate in repeat

d Ghali, G. (1993). Fluometuron: RfD/Peer Review Repo rt, dated December 9, 1993; TXR No. 010710.Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 23 of 33 Table A.2.3. Toxicity Profile of Fluometuron

Study Type MRID No. Results

Salmonella typhimurium Acceptable/guideline assays +/- S9

Mouse lymphoma 45522002 (1988) EMS 12 (1):85-154 Negative up to lethal concentrations (1000 μg/mL –S9; 800 μg/mL +S9)

870.5395 Micronucleus

assay Chinese hamster bone marrow 40882102 (1988) 0, 1000, 2000 & 4000 mg/kg Acceptable/guideline Not clastogenic or aneugenic up to 4000 mg/kg

870.5500 Unscheduled DNA Synthesis Primary rat hepatocytes 42017303 (1989) Acceptable/guideline Fluometuron did not induce UDS in primary rat hepatocytes up to precipitating concentrations ( ≥ 537.5 μg/mL –S9).

870. 6200a Acute neurotoxicity

rats Data waiver granted by HASPOC (Habiba, U, 2015; TXR No. 0057314).

870.6200b 90 Day neurotoxicity screening battery Data waiver granted by HASPOC (Habiba, U, 2015; TXR No. 0057314).

870.7485
Metabolism-Rat 40190702 (1986) Acceptable/guideline Single oral dose 0.5 & 100 mg/kg radiolabeled or after preconditioning with 14 daily doses of 0.5 mg/kg Single oral doses (0.5 & 100 mg/kg) of radiolabeled or to a single or dose (0.5 mg/kg) following a preconditioning period of 14 daily 0.5 mg/kg doses of fluometuron were analyzed. Fluometuron is metabolized by oxidative processes to yield a variety of ring hydroxylated metabolites, which can be excreted directly or go on to further metabolism and/or conjugation priorto their ultimate excretion. Conjugated metabolites include betaglucuronides or aryl sulfates. This study can be assessed along with MRID 40047403 to describe the metabolism of Fluometuron.

870.7485
Metabolism-Rat 40190702 (1986) Acceptable/guideline Single oral dose 0.5 & 100 mg/kg radiolabeled or after preconditioning with 14 daily doses of 0.5 mg/kg Following exposure to single oral doses (0.5 & 100 mg/kg) of radiolabeled fluometuron or to a single oral dose (0.5 mg/kg) following a preconditioning period of 14 daily 0.5 mg/kg doses, rats rapidly excreted the radio label, mainly in the urine, with the majority of that excreted in the urine occurring within the first 24 hrs following dosing. Urinary excretion was slightly dose-dependent, but no significant sex differences was observed. A small percentage (6-1 2%) of the dose was excreted in the feces. The highest concentration of radio label was associated with the red blood cells, with the well-perfused tissues displaying the next highest concentrations. Radio label was distributed to all tissues measured. The concentration of radiolabel remaining in the tissues at 168 hrs was dose-related and represented less than 0.2% of the administered dose. The overall recovery of radiolabel was approximately 90%.

870.7800ImmunotoxicityFemale Rat Data waiver granted for immunotoxicity (Habiba, U, 2013; TXR No. 0056795).Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 24 of 33 

### Attachment 3: Summary of Toxicological Doses and Endpoints for Fluometuron (From 2005 Risk Assessment).

Table A.3.1. Summary of Toxicological Doses and Endp oints for Fluometuron Human Health Risk Assessments a

Exposure Scenario Point of Departure (POD) Uncertainty/ FQPA Safety Factors FQPA Safety Factor Level of Concern for Risk Assessment Endpoint for Risk Assessment

Dietary Risk Assessments

Acute Dietary females 13-49

years NOAEL= 10 mg/kg UF A =10x UF H =10x FQPA SF=1x Acute RfD = Acute PAD

= 0.1 mg/kg/day MRID 00163710/42397601 Acute- Developmental, Rat LOAEL=100 mg/kg/day, based on delayed urinary system development.

Chronic Dietary all populations NOAEL = 0.55 mg/kg/day UF A =10x UF H =10x FQPA SF=1x Chronic RfD = Chronic PAD

= 0.005 mg/kg/day MRID 00163772 Chronic- Chronic/Carci nogenicity, Rat LOAEL=17.2 mg/kg/day, based on increased splenic hemosiderin pigment deposition in both sexes.

Incidental Oral: No Residential Uses are Proposed for Fluometuron.

Dermal Exposure: Short-Term Oral NOAEL = 10 mg/kg/day (DAF=10%) b UF A =10x UF H =10x FQPA SF=1x LOC for MOE=100 MRID 00163710/42397601 Developmental , Rat LOAEL = 100 mg/kg/day, based on delayed urinary system development.

Dermal Exposure:IntermediateTerm Oral NOAEL = 10 mg/kg/day (DAF=10%) b UF A =10x UF H =10x FQPA SF=1x LOC for MOE=100 MRID 00019035 Subchronic , Dog LOAEL = 150 mg/kg/day, based on inflammatory reactions in the liver and kidney

Dermal Exposure: Long-Term No uses currently support a long-term dermal endpoint

.

Inhalation Exposure: Short-Term Oral NOAEL= 10 mg/kg/day (IAF=100%) UF A =10x UF H =10x FQPA SF=1x LOC for MOE=100 MRID 00163710/42397601 Developmental , Rat LOAEL = 100 mg/kg/day, based on delayed urinary system development.

Inhalation Exposure: Intermediate

Term Oral NOAEL= 10 (IAF=100%) UF A =10x UF H =10x FQPA SF=1x LOC for MOE=100 MRID 00019035 Subchronic, Dog LOAEL =150 mg/kg/day, based on inflammatory reactions in the liver and kidney.

Inhalation Exposure: Long-term No uses currently support a long-term inhalation endpoint.

Cancer Not mutagenic. Classified as Group C (Possible Human Carcinogen) with a Q 1 * (mg/kg/day) -1 of 1.80 x 10 -2 inFluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 25 of 33 Table A.3.1. Summary of Toxicological Doses and Endp oints for Fluometuron Human Health Risk Assessments a

Exposure Scenario Point of Departure (POD) Uncertainty/ FQPA Safety Factors FQPA Safety Factor Level of Concern for Risk Assessment Endpoint for Risk Assessment

human equivalents (3/4's scaling factor to convert from animals to humans). Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra species). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable . DAF = dermal absorption factor. IAF = inhalation absorption factor.

a Data were extracted from Table 4, Toxicology Endpoints for Fluom eturon, Reaves, E. and Nielson , A. Fluometuron: Revised HED Risk Assessment for Phase III of the Reregistration Elig ibility Decision (RED). [PC Code 035503, DP Barcode 341152], dated February 1, 2005.

b A 21-Day dermal toxicity study (MRI D 00160763) exposed New Zealand White rabbits dermally at 0, 10, 100, or 1000 mg/kg/day for 3 weeks and caused no systemic compound-related changes in males or female at any dose level [NOAEL = 1000 mg/kg/day (HDT)]. Using the oral developmental rabbit stud y LOAEL of 100 mg/kg/day and the rabbit 21-day dermal study NOAEL (since no LOAEL establis hed) of 1000 mg/kg/day, the estimated upper bound dermal absorption factor (DAF) is 10 (100 mg/kg/day  1000 mg/kg/day).Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 26 of 33 

### Attachment 4: Summary of Registered Uses for Fluometuron.

Table A.4.1. Summary of Registered Uses for Fluometuron
Use site/Crop [EPA Reg. No.] 1 Application Equipment Maximum Application Rate (lb ai/A) Max rate per
crop season

(lb ai/A) Max # apps/crop

season PHI (days) REI (hours)

Cotton [66222-32; 66222-181; 66330-260; 83529-33; NC120002] Ground Aerial 2 3 2 60 24

Wildflowers [NC 120002] Ground Aerial Handheld 1 (0.1 lbs ai/gallon) NS NS NA 24

NS=Not stated; NA=Not applicable.

1 EPA Reg No 11603-31 and 82633-19 are technical registrations.Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 27 of 33 

### Attachment 5: DFR Waiver Criteria.
In accordance with 40CFR158, DFR data are requi red for all occupational (e.g., crop, nursery, greenhouse use sites) or reside ntial (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post-application expos ure to foliage. In the absence of chemical-specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure A ssessment includes an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a folia r application (FAR). Th is value is based on an analysis of 19 DFR studies. Since that time, th e Agricultural Re-entry Task Force has submitted information (MRID 49299201) that corrects an app lication rate error ma de in the original submission of “ARF039 – Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result of this submission, the default value of 25% was not change d as it still reflects a high-end, conservative value. However, it is important to note that the range of FAR values wa s revised from 2% - 89% to 2% - 47%. In the data, a large range of tran sferability is observed and this variability can potentially be attributable to many factors such as active ingredient; form ulation; field conditions in the studies; weather conditi ons (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in FAR values is not expected when considering DFR data for a single chemi cal. Because DFR data are not available for fluometuron, EPA is using the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value fo r fluometuron (i.e., there is a small chance that the FAR value may exceed the applicable default va lue), it is likely thatthe health-protective aspects of EPA’s occupational post-applic ation assessment methodology will more than compensate for this potential uncertainty. Fo r example, when asse ssing residential and occupational post-application exposure to gardens and ornamentals, EPA assumes the following: exposures occur to zero-day (i.e., day of application ) re sidues every day of the assessed exposure duration (i.e., EPA assumes th at no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform the same post-application activities performed in the transfer coefficient study day after day (e.g., we eding, harvesting, pruning, etc.); and individuals engage in these post-applicati on activities for a high-end amount of time every day (represented by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above a nd the potential compounding nature of these conservatisms, EPA is able to re ly upon the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the highest estimated occ upational post-applicati on exposure using default DFR values for fluometuron is minimal in comparison to the level of concern (i.e., the calc ulated MOE is greater than 2 times higher than the level of concern, MOE = 730 compared to the LOC of 100); EPA is waiving the 40CFR DFR data requirement. In this instance, it is unlikely that chemical-specific DFR data would be needed to further refine e xposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pesticide residues for fluometuron.
Based on the Agency's current practices, a quant itative occupational post- application inhalation exposure assessment was not performed for fluometuron at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation expos ure assessment for fluometuron.Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 28 of 33 

### Attachment 6: Fluometuron Intern ational Residue Limit Status Sheet.

Fluometuron (PC Code 035503) Summary of US and International Tolerances and Maximum Residue Limits. Residue Definition : US Canada Mexico 1 Codex 40 CFR §180.229 Primary Crops: fluometuron, N

, N -dimethyl- N '-[3- (trifluoromethyl)phenyl]urea, and its metabolite, trifluoromethylaniline (TFMA) determined as TFMA

Livestock: fluometuron, N

, N

-dimethyl- N '-[3- (trifluoromethyl)phenyl]urea, and its metabolites determined as TFMA and the hydroxylated metabolites: CGA-236431, 1- (4-hydroxy-3-trifluoromethylphenyl)urea; CGA-236432, 1- methyl-3-(4-hydroxy-3-trifluoromethylphenyl)urea; and CGA-13211, 1,1-dimethyl-3-(4-hydroxy-3- trifluoromethylphenyl) urea None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Primary Crops Cotton, gin byproducts 3.5 Cotton, undelinted seed 1.0 Livestock Cattle, meat byproducts 0.1 Egg 0.1 Goat, meat byproducts 0.1 Hog, meat byproducts 0.1 Horse, meat byproducts 0.1 Milk 0.02 Poultry, fat 0.1 Poultry, meat 0.1 Poultry, meat byproducts 0.1 Sheep, meat byproducts 0.1 Completed: M. Negussie; 10/30/15

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

(d) Indirect or inadvertent residues. Tolerances are established for the combined residues of th e herbicide fluometuron, N

, N -dimethyl- N '-[3- (trifluoromethyl)phenyl]urea, and its metabolite, trifluoromethylaniline (TFMA) determined as TFMA, in or on the following food commodities. Commodity Parts per million

Grain, cereal, forage, fodder, and straw group 16, forage 3.0 Grain, cereal, forage, fodder, and straw, group 16, stover 6.0 Grain, cereal, group 15 0.5 Peanut 0.1 Peanut, hay 4.0 Peanut, meal 0.2 Soybean, forage 3.0 Soybean, hay 3.0 Soybean, seed 2.0 Rice, hulls 1.0 Wheat, milled byproducts 1.0Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 29 of 33 

### Attachment 7. Bovine Liver and Milk Hydr oxylated Metabolite Storage Stability Data

HED previously requested storage stability data for the hydroxylat ed metabolites of fluometuron (CGA-236431, CGA-236432, CGA-13211) in ruminant m ilk and muscle (up to 269 days) and egg and poultry tissues (approximately 4 months; Memo, S. Ary, 30-NOV-2004; D300553). Subsequently, the ChemSAC recommended that storage stability stud ies on the hydroxylated metabolites be conducted for residues in rumina nt liver and milk samples and that any requirement for additional poultry data be deferr ed until the required ruminant storage stability data had been submitted and reviewed (Che mSAC Minutes, 17-OCT-2007). ChemSAC also recommended that if the ruminant storage stabil ity data indicated that residues were stable, a poultry feeding study and storage stab ility data for egg and poultry tissues would not be required.

Acceptable storage stability data for bovine live r and milk have been submitted to the Agency (MRID 48491201) and these deficiencies are now reso lved. The results of the study showed that residues of the hydroxyfluometuron meta bolites CGA-13211, C GA-235431, and CGA-235432 are stable for at least 12.9 months for liver and 12.0 months for milk when stored at or below -12 °C. Since the ruminant liver and milk data indi cated that residues are stable for the storage duration, a poultry feeding study an d storage stability data for egg and poultry tissues are not required at this time. The bovine liver a nd milk results are summarized below.

Samples of bovine liver and milk were fortified with CGA-13211, CGA-236431, and CGA236432, at a level of 0.50 ppm for bovine liver and milk and put into storage at ~-12 °C. At intervals of 0, 1, 10, 12, and 13 months for liver and 0, 1, 3, 6, and 12 months for milk, stored samples and freshly fortified samples were analyzed for residues of CGA-13211, CGA-236431, and CGA-236432 using the enforcement me thod AG-678, a high performance liquid chromatography (HPLC) with fluorescence dete ction or liquid chromatography with mass spectrometric detection (LC/MS/MS) method. Method AG-678 was previously reviewed by the Agency (refer to 44623201.der; DP# 249612, 11/11/04, A. Nielsen). All bovine liver samples (except 0-day and 1-month) were analyzed by LC/MS/MS. All milk samples and 0-day and 1- month liver samples were analyzed by HPLC with fluorescence dete ction. Acceptable concurrent recoveries were repor ted for bovine liver and milk samp les at fortification levels of 0.50 ppm, thus validating the method. The limit of quantitation (LOQ) was 0.02 ppm per analyte for bovine liver and 0.01 ppm per analyte for milk

Table A.7.1. Stability of Hydro xyfluometuron Metabolite Residues in Bovine Liver and Milk During Storage at ~-12 °C. Commodity Storage Duration Days (Months) Fortification Level (ppm) Recovered Residues (ppm) Mean Recovery (%) Mean Concurrent Recovery 1 (%) Corrected Recovery 2 (%)

CGA-13211
Liver 0 0.50 0.4413, 0.4408 88 88 -- 35 (1.2) 0.3224, 0.3290 65 82 81 316 (10.4) 0.2970, 0.3476 64 82 78 365 (12.0) 0.4006, 0.2772 68 80 87 392 (12.9) 0.3798, 0.4251 80 89 91
Milk 0 0.50 0.5596, 0.5340 110 110 -- 33 (1.1) 0.4654, 0.4792 94 57 198 90 (3.0) 0.3836, 0.4549 84 96 89 181 (6.0) 0.4029, 0.4212 82 82 100 365 (12.0) 0.4321, 0.4905 92 93 100Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 30 of 33 Table A.7.1. Stability of Hydro xyfluometuron Metabolite Residues in Bovine Liver and Milk During Storage at ~-12 °C. Commodity Storage Duration Days (Months) Fortification Level (ppm) Recovered Residues (ppm) Mean Recovery (%) Mean Concurrent Recovery 1 (%) Corrected Recovery 2 (%)
CGA-236431
Liver 0 0.50 0.4166, 0.4562 87 87 -- 35 (1.2) 0.3126, 0.3259 64 91 70 316 (10.4) 0.3322, 0.3531 69 81 85 365 (12.0) 0.3885, 0.2431 63 75 85 392 (12.9) 0.3565, 0.4065 76 79 97
Milk 0 0.50 0.5639, 0.4501 102 102 -- 33 (1.1) 0.4173, 0.4358 85 53 179 90 (3.0) 0.4000, 0.4694 87 93 93 181 (6.0) 0.4127, 0.4207 83 85 98 365 (12.0) 0.4664, 0.4781 94 95 99
CGA-236432
Liver 0 0.50 0.4037, 0.4358 84 84 -- 35 (1.2) 0.2829, 0.3235 61 92 66 316 (10.4) 0.3557, 0.3620 72 87 82 365 (12.0) 0.3985, 0.2784 68 79 87 392 (12.9) 0.3892, 0.4347 82 87 95
Milk 0 0.50 0.5676, 0.4309 100 100 -- 33 (1.1) 0.4226, 0.3992 82 50 186 90 (3.0) 0.3809, 0.4372 82 88 93 181 (6.0) 0.3846, 0.4153 80 84 95 365 (12.0) 0.4687, 0.4863 96 95 101

1 Separate stored samples we re not analyzed on Day 0.

2 Corrected for mean concurrent recovery.Fluometuron Registration Review Human Health Assessment Scoping Document D430248__________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________Page 31 of 33Attachment 8. Status of Chemistry Deficiencies Identified During ReregistrationSeveral data requirements were identifiedas part of Reregistration (E. Reaves, 2/1/2005; D341152). Aside from the removal ofa gin trash feedingrestriction from one label (EPA Reg. No. 66330-260), the chemistry data deficiencies identified as part of reregistration havebeen adequatelyaddressed.Table A.8.1. Status of Previously Identified Chemistry Data Deficiencies.Guideline PreviouslyIdentified Data Deficiencies1Scoping Comments860.1200Directions forUseLabel revisions are required for cotton and rotational crops.Cotton: The registrant must amend fluometuron labels with registered uses on cotton toreflect the test parameters for which adequate data are available. Product labels shouldbe amended to specify: one preemergence treatment at a maximum rate of 2.0 lb ai/A,one early postemergence treatment at a maximum rate of 1.6 lb ai/A, and one laybytreatment at a maximum rate of 2.0 lb ai/A.A maximum seasonal rate of 5.6 lb ai/Ashould be established.The use patterns are summarized in Attachment 4.The maximum use seasonal use rate is 3 lb ai/A onall labels, which is lower than the seasonal rate of5.6 lb ai/A that was indicated in the RED. Thecurrent labels indicate that the maximum numberof applications per year is 2. The labels includepreplant, preemergence, and postemergenceapplication instructions that are based on soil type.The treatments rates are equivalent to or less thanthe rates indicated in the RED for the specifictiming of application. Label revisions for theapplication rate and number of applications are notrequired at this time.In addition, because cotton gin trash is a livestock feed item not under control of thegrower, the feeding restriction must be removed from the product labels.The Flomet 4L label (EPA Reg. No. 66330-260)still contains a gin trash livestock feedingrestriction that should be removed.Rotational Crops: Label amendments for all fluometuron end-use products are requiredto specify the appropriate plantback intervals for rotational crops. Adequate data areavailable to support the following intervals: three months for wheat; eight months forfield corn, sweet corn, and peanuts; and nine months for rice, grain sorghum, andsoybeans.The appropriate plantback intervals are included inthe registered labels. If the registrant wishes tosupport rotational crops and plantback intervalsother than those listed, then additional rotationalcrop field trials must be conducted.860.1340ResidueAnalyticalMethod -AnimalCommoditiesThe registrant must either improve Method AG-519A or develop a new method capableof determining fluometuron residues that may be converted to TFMA in livestockcommodities. The proposed enforcement method should undergo an independentlaboratory validation according to PR Notice 96-1 dated 2/7/1996. Once a successfulindependent laboratory validation has been completed, the proposed method will besubject to a methodtrial by the Agency.The Registrant submitteda waiver request for arevised Method AG-519A, and HED reviewed thesupporting rationale and recommended that thestudy requirement be waived (Memo, P. Barnes,23-APR-2009; D300532). The ACB has reviewedmethod data (without laboratory validation) forMethods 519, 519A, AG-678, AG-528, and AG529 and concluded that the methods appear tomeet the 860.1340 Residue Chemistry TestFluometuron Registration Review Human Health Assessment Scoping Document D430248_______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________Page 32 of 33Table A.8.1. Status of Previously Identified Chemistry Data Deficiencies.Guideline PreviouslyIdentified Data Deficiencies1Scoping CommentsGuidelines for acceptable tolerance enforcementmethods (Memo, C. Stafford, 13-MAR-2009;D300532).860.1380StorageStability DataSamples of cottonseed and cotton gin byproducts that are to be collected from therequired field trials should be storedunder frozen storage conditions and analyzedwithin the storage interval for which residues of fluometuron, determined as TFMA,have been found to be stable (ca. twenty months).The cottonseed and cotton gin byproduct data areno longer required because the DF formulationshave been cancelled.Fluometuron was stable in beef muscle andin liver stored frozen for two years.Fluometuron was stable in milk stored frozen for up to one year. Additional data arerequired on the stability of the hydroxylated metabolites (CGA-236431, CGA-236432,CGA-13211) in milk and muscle. The storage intervals and conditions must beapproximate to those of the ruminant feeding study.Acceptable storage stabilitydata for bovine liverand milk have been submitted (MRID 48491201)and these deficiencies are now resolved. CGA13211, CGA-235431, and CGA-235432 are stablefor at least 12.9 months for liver and 12.0 monthsfor milk when stored at or below -12 °C.The egg and poultry tissue samples from an existing poultry feeding study were storedfrozen for ca. four months. A study must be conducted investigating the stability of thehydroxylated metabolites (CGA-236431, CGA-436432, CGA-13211, and theirconjugates) following storage under the same storage conditions and for the sameinterval.Since the ruminant liver and milk data indicatedthat residues are stable for the storage duration, apoultry feeding study and storage stability data foregg and poultry tissues are not required at this time(ChemSAC Minutes, 17-OCT-2007).860.1500Crop FieldTrialsCottonseedand ginbyproductsAdditional data depicting residues of fluometuron and its metabolites determined asTFMA and the hydroxylated metabolites in/on cottonseed are required. Cottonseedshould be harvested/collected at normal maturity following applications of the DFformulation according to the followingtreatment schedule: one preemergenceapplication at 2.0 lb ai/A, one early postemergence foliar application (when plants are3-6 in high) at 1.6 lb ai/A, and one layby foliar application at 2.0 lb ai/A. A minimumof six trials must be conducted. The cotton plants must be harvested by commercialequipment (or similar thereof) to provide anadequate representation of plant residuefrom the ginning process. Stripper harvesting should be used for three trials andmechanical picker harvesting should be used for three trials. The six trials shouldrepresent the principalU.S. growing regions.The DF formulations have been cancelled;therefore, these data are no longer required. Thesedata may be required in the future if the Agencyreceives petitions for the useof DF formulations.860.1900FieldRotationalCropsRotational Crops: Label amendments for all fluometuron end-use products are requiredto specify the appropriate plantback intervals for rotational crops. Adequate data areavailable to support the following intervals: three months for wheat; eight months forfield corn, sweet corn, and peanuts; and nine months for rice, grain sorghum, andsoybeans.The registered labels reflect the plantback intervalsthat are supported by the rotational crop data. Ifthe registrant wishes to support rotational cropsand plantback intervals other than those listedabove, then additional rotational crop field trialsmust be conducted.1Data needs were identified in Table 6 of Memo, E. Reaves, 01-FEB-2005; D341152.Fluometuron Registration Review Human Health Assessment Scoping Document D430248

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Page 33 of 33 

### Attachment 9. Submittal of Analyt ical Reference Standards (860.1650)

Analytical reference standards for parent fluom eturon are currently available in EPA’s National Pesticide Standards Repository (NPSR) and expire on 6/30/2016. Analytical reference standards are currently unavailable in EPA’s NPSR for th e following metabolites: trifluoromethylaniline (out of stock); CGA-236431 (expired on 6/26/ 2014); CGA-236432 (expired on 6/26/2014); and CGA-13211 (expired on 6/26/2014) (Email communication with G. Verdin of BEAD/ACB on 11/9/2015). The registrant is required to mainta in reasonable amounts of the reference standards for fluometuron and its metabolites in the NPSR as long as tolerances remain published in 40CFR §180.229. When necessary, new reference stan dards, or updated certif icates of analysis (COAs), should be sent to the ACB, which is locate d at Fort Meade, MD. It should be sent to the attention of either Theresa Cole or Thuy Nguyen at the address listed belo w, along with a letter of transmittal. Please note that the full 9-digit ZIP Code is required, or the mail will be returned to the registrant.

USEPA National Pesticide Standards Repository Analytical Chemistry Branch/BEAD/OPP 701 Mapes Road Fort George G. Meade, MD 20755-5350

The letter of transmittal should include the assay of the standard, name of the analytical method used, a statement of principal impurities, purification procedures employed, storage requirements, and special precautions for safe handling. Replacement of standards, or updated COAs, may be required periodically if supplies are exhausted, if the standards expire, or if decomposition occurs during storage. Material Safety Data Sheets (MSDSs) must accompany all analytical standards as specified by the Occupa tional Safety and Health Administration (OSHA) in 29CFR §1910.1200.Fluometuron [PC Code 035503]/ Makhteshim-Agan of North America



### B.7.8.3 Stability of Residues Prior to Analysis

B.7.8.3 Bovine Liver and Milk

Document ID: Report:

Guidelines:

GLP Compliance:

Acceptability:

Evaluator: 

### MRID No. 48491201 Barker, W

. (2011) Determination of Hydroxyfluometuron Metabolites Stability in Frozen Liver and Milk. Study ID#: 09-0036. Unpublished study prepared by Makhteshim-Agan of North America, Inc. 178 p. EPA OCSPP Harmonized Test Guideline 860 .13 80 Storage Stability Data (August 1996)
PMRA Regulatory Directive DIR98-02

- Residue Chemistry Guidelines, Section 5

- Storage Stability Data OECD Guideline 506 Stability of Pesticide Residues in Stored Commodities (October 2007)
No deviations from regulatory requirements were reported which would have an impact on the validity of the study. The study is considered scientifically acceptable. The acceptability of this study for regulatory purposes is addressed in the U.S. EPA Human Health Scoping Document (D430248; D391415)

. 1 , /' 11 

### Julie L. 

### Van Alstine, MPH, Environmental Health Scientist

, _J t.1 } ..1-,,_, 

### V w..... 

### ./r'------- 

### Risk Assessment Branch 6 (RAB 6)/Health Effects Division (HED)

Note: This Data Evaluation Record (DER) was originally prepared under contract b y Versar

, Inc

. (6850 Versar Center

, Springfield, VA 22151; submitted 8 / 5115)

. The D E R has be e n reviewed by HED and revi se d to reflect current Office of P est icide Programs (OPP) policie s.



### EXECUTIVE SUMMARY



### Makhteshim-Agan of North America

, Inc. has submitted the results of a storage stability study of the hydroxyfluometuron metabolites CGA-13211, CGA-236431, and CGA-236432 in bovine liver and milk

. Samples of bovine liver and milk were fortified with CGA-13211

, CGA-236431, and CGA-236432, at a level of 0

. 50 ppm for bovine liver and milk and put into storage at**~-12** 

### °C. At intervals of 0, 1, 10, 12, and 13 months for liver and 0, 1, 

### 3, 6

, and 12 months for milk, stored samples and freshly fortified samples were analyzed for residues of CGA-13211, CGA236431, and CGA-236432.

At each storage interval, hydroxyfluometuron metabolites, CGA-13211, CGA-236431, and CGA-236432

, were determined using Method AG-678

, a high performance liquid chromatography (HPLC) with fluorescence detection or liquid chromatography with mass spectrometric detection (LC/MS/MS) method to determine residues of CGA-13211, CGA236431

, and CGA-236432. Acceptable concurrent recoveries were reported for bovine liver and milk samples at fortification levels of 0.50 ppm, thus validating the method. The limit of quantitation (LOQ) was 0.02 ppm per analyte for bovine liver and 0.01 ppm per analyte for milk.

Under these conditions

, residues ofhydroxyfluometuron metabolites, CGA-13211, CGA236431, and CGA-236432, were stable in bovine liver at 12.9 months and milk at 12.0 months.

EPA MRID #: 48491201

Page 1 of6Fluometuron [PC Code 035503]/ Makhteshim-Agan of North America

EPA MRID #: 48491201

Page 2 of 6 

### I. MATERIALS AND METHODS

A. MATERIALS

1. Test Material

Table B.7.8.3-1. Nomenclature for Fl uometuron and Metabolites of Interest.

Common name Fluometuron Identity N

, N

-dimethyl- N ’-(3-(trifluoromethyl)phenyl)urea
CAS no. 2164-17-2 Company experimental name Not applicable Other synonyms (if applicable) Not applicable

Metabolite CGA-13211 Identity 1,1-dimethyl-3-( α , α , α -trifluoromethyl-4-hydroxy- m -tolyl)urea
CAS no. Not available Company experimental name ET-2613 Other synonyms (if applicable) Not applicable

Metabolite CGA-236431 Identity ( α , α , α -trifluoromethyl-4-hydroxy- m -tolyl)urea
CAS no. Not applicable Company experimental name ET-2614 Other synonyms (if applicable) Not applicable

Metabolite CGA-236432 Identity 1-methyl-3-( α , α , α -trifluoromethyl-4-hydroxy- m -tolyl)urea
CAS no. Not applicableFluometuron [PC Code 035503]/ Makhteshim-Agan of North America

EPA MRID #: 48491201

Page 3 of 6

Table B.7.8.3-1. Nomenclature for Fluometuron and Metabolites of Interest. Company experimental name ET-2612 Other synonyms (if applicable) Not applicable



### 2. Test Commodity

Livestock Matrix: Bovine liver and milk.

B. STUDY DESIGN

1. Test Procedure

The stock solutions of CGA-13211, CGA-236431, and CGA-236432 (1000 μg/mL) were diluted with methanol and stored frozen. Untreated samples of bovine liver and whole milk were acquired from a grocery store. Liver samples were ground in a Hobart food processor and whole milk was thoroughly shaken before for tification with CGA-13211, CGA-236431, and CGA236432.

A total of 33 sub-samples of each of the two different matrices were weighed into polyethylene bottles. For each matrix, 4 sub-samples were used as control samples and procedural recovery samples. The remaining 2 sub-samples were for tified with each analyt e individually at 0.50 ppm and were to be used for st orage stability samples.

On the day of sample fortifica tion (0 day), a single control an d duplicate samples fortified with 0.50 ppm of CGA-13211, CGA-2364 31, and CGA-236432 were analyzed. The remaining samples were transferred to freezer storage (-12 °C) until required for analysis. Liver samples were analyzed after storage intervals of appr oximately 0, 1, 3, and 12 months (with a 10 and 13 month added); actual storage peri ods were 0 days (0 months), 35 days (1.2 months), 316 days (10.4 months), 365 days (12.0 months), and 392 days (12.9 months). Milk samples were analyzed after storage intervals of approximate ly 0, 1, 3, 6, and 12 months; actual storage periods were 0 days (0 months), 33 days (1.1 months), 90 days (3.0 months), 181 days (6.0 months), and 365 days (12.0 months). At the specified storag e interval, a set of samples for each livestock matrix was removed from frozen storage for anal ysis. The sample set for each storage interval consisted of the same number of samples as th e sample set from the day-0 analysis. No concurrent recovery samples were run for the day-0 sampling set.

2. Description of Analytical ProceduresFluometuron [PC Code 035503]/ Makhteshim-Agan of North America

EPA MRID #: 48491201

Page 4 of 6 

### Samples of bovine liver and milk were an alyzed for residues of CGA-13211, CGA-236431, and CGA-236432 using the proposed enforcement met hod, AG-678, that was previously reviewed by the Agency (refer to 44623201.der; DP# 249612, 11/11/04, A. Nielsen). A complete description of the method was included in the submission. All bovine liver samples (except 0-day and 1- month) were analyzed by LC/MS/MS. All milk samples and 0-day and 1-month liver samples were analyzed by HPLC with fluorescence detection.

For bovine liver, samples were refluxed with methanol (MeOH):5% acetic acid (80:20; v:v). Following filtration, an aliquot of the extract was evaporated to the remove the organic solvent and diluted with water. The aqueous so lution is then hydrolyzed with enzymes ( β -glucuronidase and sulfatase) and cleaned up on a C18 solid phase extraction (SPE) column, if necessary (HPLC analysis with fluorescence dete ction only). Residues were el uted with MeOH:0.1% acetic acid (60:40, v:v). The eluate was ev aporated to dryness and partiti oned into ethyl acetate:hexane (80:20, v:v). The extracts were cleaned up on a C18 SPE column (HPLC analysis with fluorescence detection only). Residues were el uted with ethyl acetate :MeOH:acetonitrile (ACN) (270:20:10; v:v:v). The eluate wa s evaporated near dryness, redissolved in a mixture of acetic acid (0.1%):MeOH (70:30, v:v) to yield the final fraction. An a liquot of the final fraction was injected into an HPLC system for quantitation of residues by fluorescen ce detection (0-day and 1-month liver samples only) or LC/MS/MS (all liver samples, except 0-day and 1-month).

For bovine milk, samples were extracted with me thanol. Following filtration, an aliquot of the extract was evaporated to the remove the organi c solvent and diluted with water. The aqueous solution was then hydrolyzed with enzymes ( β -glucuronidase and sulfat ase), partitioned into ethyl acetate:hexane ( 80:20, v:v), and cleaned up on a C18 solid phase extraction (SPE) column. Residues were eluted with ethyl acetate: MeOH:ACN (270:20:10, v:v:v) . The eluate was evaporated near dryness, redi ssolved in a mixture of acetic acid (0.1%):MeOH (70:30, v:v) to yield the final fraction. An ali quot of the final fraction was inje cted into an HPLC system for quantitation of residues by fluorescence detection.

For LC/MS/MS, the following ion transiti ons were monitored for quantitation: m/z 219 → 156 for CGA-13211, m/z 247 → 183 for CGA-236431, and m/z 233 → 156 for CGA-236432. The reported LOQs for each analyte were 0.02 ppm for liver and 0.01 ppm for milk.

II. RESULTS AND DISCUSSION

Method performance was evaluated by use of c oncurrent recovery samples by fortification bovine liver and milk at 0.50 ppm. All recoveries were generally within the acceptable range of 70-120%; therefore, the method wa s considered valid for the an alysis of hydroxyfluometuron and metabolite residues in bovine matrices (Table B.7.8.3-2). Concurrent recoveries were used to correct the residues in the stored samples.

The detector response was linear (coefficient of determination, r 2 

### ≥ 0.9849 for CGA-13211, r 2


### ≥ 0.9984 for CGA-236431, and r 2 

### ≥ 0.9866 for CGA-236432 within the range of 0.01-0.50 μg/mL). Representative chromatograms of cont rol samples, fortified samples, and treated samples were provided. The control chromatogram s generally had no peaks of interest above the chromatographic background. Residues in controls were below the LOQ ( ≤ 0.02 ppm) for liverFluometuron [PC Code 035503]/ Makhteshim-Agan of North America

EPA MRID #: 48491201

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### and below the LOQ ( ≤ 0.01 ppm) for milk with the exception of one untreated milk sample at 33 days bore detectable resi dues of CGA-236431 at 0.0142 ppm.

Table B.7.8.3-2. Summary of Procedural/Concurrent Recoveries of Hydroxyf luometuron Metabolites, CGA-13211, CGA-236431, and CGA-236432 from Bovine Liver and Milk.

Matrix Fortification Level (ppm) Storage Interval (days) Sample size (n) Recoveries 1 (%) Mean ± Std. Dev. 2 (%)

CGA-13211 Liver 0.50 0 2 88, 88 88 35 2 94, 70 82 316 2 79, 85 82 365 2 74, 85 80 392 2 95, 84 90 Milk 0.50 0 2 112, 107 110 33 2 34, 79 57 90 2 104, 88 96

181 3 2 78, 87 83 365 2 88, 97 93
CGA-236431 Liver 0.50 0 2 83, 91 87 35 2 92, 91 92 316 2 81, 81 81 365 2 71, 79 75 392 2 85, 74 80 Milk 0.50 0 2 113, 90 102 33 2 36, 69 53 90 2 91, 95 93

181 3 2 81, 90 86 365 2 90, 101 96
CGA-236432 Liver 0.50 0 2 81, 87 84 35 2 94, 91 93 316 2 87, 87 87 365 2 73, 85 79 392 2 92, 82 87 Milk 0.50 0 2 114, 86 100 33 2 34, 65 50 90 2 87, 89 88

181 3 2 79, 89 84 365 2 89, 101 95

1 Concurrent recoveries were corrected for apparent residues in controls.

2 Standard deviation is not calculated for sample sizes < 3.

3 The fresh fortification and stored fortific ation recoveries reported fo r two samples of milk from the 181-day storage interval in the summary tables (p. 10 & 19) in the subm ission were reversed. These values are th e recoveries found in the raw data on p. 154-155.



### The results of the storage stab ility study are presented in Tabl e B.7.8.3-3. The results of the study showed that residues of hydroxyfluom eturon metabolites, C GA-13211, CGA-235431, and CGA-235432, are stable for at least 12.9 months fo r liver and 12.0 months for milk when stored at or below -12 °C.Fluometuron [PC Code 035503]/ Makhteshim-Agan of North America

EPA MRID #: 48491201

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Table B.7.8.3-3. Stability of Hydroxyfluometuron Metabolite Residues in Bovine Liver and Milk During Storage at ~-12 °C. Commodity Storage Duration Days (Months) Fortification Level (ppm) Recovered Residues (ppm) Mean Recovery (%) Mean Concurrent Recovery 1 (%) Corrected Recovery 2 (%)

CGA-13211
Liver 0 0.50 0.4413, 0.4408 88 88 -- 35 (1.2) 0.3224, 0.3290 65 82 81 316 (10.4) 0.2970, 0.3476 64 82 78 365 (12.0) 0.4006, 0.2772 68 80 87 392 (12.9) 0.3798, 0.4251 80 89 91
Milk 0 0.50 0.5596, 0.5340 110 110 -- 33 (1.1) 0.4654, 0.4792 94 57 198 90 (3.0) 0.3836, 0.4549 84 96 89 181 (6.0) 0.4029, 0.4212 82 82 100 365 (12.0) 0.4321, 0.4905 92 93 100
CGA-236431
Liver 0 0.50 0.4166, 0.4562 87 87 -- 35 (1.2) 0.3126, 0.3259 64 91 70 316 (10.4) 0.3322, 0.3531 69 81 85 365 (12.0) 0.3885, 0.2431 63 75 85 392 (12.9) 0.3565, 0.4065 76 79 97
Milk 0 0.50 0.5639, 0.4501 102 102 -- 33 (1.1) 0.4173, 0.4358 85 53 179 90 (3.0) 0.4000, 0.4694 87 93 93 181 (6.0) 0.4127, 0.4207 83 85 98 365 (12.0) 0.4664, 0.4781 94 95 99
CGA-236432
Liver 0 0.50 0.4037, 0.4358 84 84 -- 35 (1.2) 0.2829, 0.3235 61 92 66 316 (10.4) 0.3557, 0.3620 72 87 82 365 (12.0) 0.3985, 0.2784 68 79 87 392 (12.9) 0.3892, 0.4347 82 87 95
Milk 0 0.50 0.5676, 0.4309 100 100 -- 33 (1.1) 0.4226, 0.3992 82 50 186 90 (3.0) 0.3809, 0.4372 82 88 93 181 (6.0) 0.3846, 0.4153 80 84 95 365 (12.0) 0.4687, 0.4863 96 95 101

1 Separate stored samples we re not analyzed on Day 0.

2 Corrected for mean concurrent recovery.



### III. CONCLUSIONS

The storage stability study with bovine liver and milk is consider ed scientifically acceptable. The results of the study showed that resi dues of hydroxyfluometuron metabolites CGA-13211, CGA-235431, and CGA-235432, are stable for at leas t 12.9 months for liver and 12.0 months for milk when stored at or below -12 °C.

REFERENCES

44623201.der; DP# 249612, 11/11/04, A. Nielsen